Background: Human HDACs represent a group of enzymes able to modify histone and non-histone proteins, which interact with DNA to generate chromatin. The correlation between irregular covalent modification of histones and tumor development has been proven over the last decades. Therefore, HDAC inhibitors are considered as potential drugs in cancer treatment. Romidepsin (FK228), Belinostat (PXD-101), Vorinostat (SAHA), Panobinostat (LBH-589) and Chidamide were approved by FDA as novel antitumor agents. Objective: The aim of this review article is to highlight the structure-activity relationships of several FK228 analogues as HDAC inhibitors. In addition, the synergistic effects of a dual HDAC/PI3K inhibition by some derivatives have been investigated. Materials and Methods: PubMed, MEDLINE, CAPLUS, SciFinder Scholar database were considered by selecting articles which fulfilled the objectives of this review, dating from 2015 till present time. Results: HDAC inhibitors have a significant role in cancer pathogenesis and evolution. Class I HDAC isoformrs are expressed in many tumor types, therefore, potent and selective Class I HDAC inhibitors are of great interest as candidate therapeutic agents with limited side effects. By structure-based optimization, several FK228 analogues [15 (FK-A5), 22, 23, 26 (FK-A11)] were identified, provided with significant activity against Class I HDAC enzymes and dose dependent antitumor activity. Compound 26 was recognized as an interesting HDAC/PI3K dual inhibitor (IC50 against p110α of 6.7 µM while for HDAC1 inhibitory activity IC50 was 0.64 nM). Conclusion: Romidepsin analogues HDAC inhibitors have been confirmed as useful anticancer agents. In addition, dual HDAC/PI3K inhibition showed by some of them exhibited synergistic effects in inducing apoptosis in human cancer cells. Further studies on FK228 analogues may positively contribute to the availability of potent agents in tumor treatment.
: Histone acetylation balance is one epigenetic mechanism controlling gene expression associated with disease progression. It has been observed that histone deacetylase 10 (HDAC-10) isozyme contributes to the chemotherapy resistance; in addition, the poor clinical outcome observed in patients with aggressive solid tumors, such as neuroblastoma, has been associated with its overexpression. Moreover, HDAC-10 selective inhibition suppresses the autophagic response, thus providing an improved risk-benefit profile compared to cytotoxic cancer chemotherapy drugs. On these bases, HDAC-10 is becoming an emerging target for drug design. Due to the rapid progress in the development of next-generation HDAC inhibitors, this review article aims to provide an overview on novel selective or dual HDAC-8/10 inhibitors, as new leads for cancer chemotherapy, able to avoid the severe side-effects of several actual approved “pan” HDAC inhibitors. A literature search was conducted in MedLine, PubMed, Caplus, SciFinder Scholar databases from 2015 to the present. Since the disclosure that the HDAC-6 inhibitor Tubastatin A was able to bind HDAC-10 efficiently, several related analogues were synthesized and tested. Both tricyclic (25-30) and bicyclic (31-42) derivatives were considered. The best pharmacological profile was shown by 36 (HDAC-10 pIC50 = 8.4 and pIC50 towards Class I HDACs from 5.2–6.4). In parallel, based on the evidence that high levels of HDAC-8 are a marker of poor prognosis in neuroblastoma treatment, dual HDAC-8/10 inhibitors were designed. The hydroxamic acid TH34 (HDAC-8 and 10 IC50 = 1.9 µM and 7.7 µM, respectively) and the hybrid derivatives 46d, 46e and 46g were the most promising both in terms of potency and selectivity. Literature surveys indicate several structural requirements for inhibitory potency and selectivity towards HDAC-10, e.g., electrostatic and/or hydrogen bond interactions with E274 and complementarity to the P(E,A) CE motif helix.
We aim to Provide facts about the vaccination coverage for combined vaccines such as MMR (Measles, Mumps and Rubella) and DTP (Diphtheria, Tetanus, Pertussis) containing vaccines in use in Albania during the last 10 years, in order to confirm the stability of immunization program. One of the reasons for coverage improvement is the use of one or two-dose vials for the administration of MMR vaccine, enabling the vaccination of children at any time, without the need of gathering them on certain days when the multi-dose vaccine vials are opened. In the last three years, according to WHO recommendations, it was noted that vaccination coverage with three doses containing DTP is at sustainable levels, always above 95%, but for our country this value goes sometimes above 98%. As for the use of pentavalent vaccine, from 2008, DTP-HepB-Hib, also the coverage of Hepatitis b vaccine is always at upper levels due to its use on 5 in 1 combination. The application of this vaccine was associated with the use of one dose vial administration, therefore one vaccine to a child. Immunization coverage for vaccines with measles component remains at very high levels for both doses of vaccine, more then 95%. Immunization coverage for vaccines with DTP component exceeds 95% rate at country level, for each district it exceeds 95% and it reaches the value of 98.5% for the last two years. During the last years the vaccine coverage is increased significantly as a result of using combined vaccine of DTP-HepB -Hib. The use of one dose vials has played an important role on sustaininig and increasing vaccination coverage.
This study evaluates the knowledge and attitudes of mothers regarding the immunization in a random sample of 100 children from Tirana, Durrës, Pogradec and Korçë, Albania. The questionnaire collected data on person answering the questionnaire, parent's educational and occupational status, parental knowledge on vaccines and vaccination and type of vaccine administration. The questions about attitudes on the utility of vaccinations were scored on a 5-point Likert scale with options ranging from ʺ1ʺ) to ʺ5ʺ). The behavior responses and the questions concerning mothers' responsibility on taking decisions regarding vaccination were in ʺyes/noʺ format and only two questions were open ones. Almost all the children were vaccinated with all the three doses of DTP and hepatitis B. In the meantime, for the optional vaccines, such as Influenza, HPV, only 2% of respondents stated that their children had been vaccinated. The results showed that the attitudes toward the utility of vaccinations for preventing infectious diseases were favorable. Most of the respondents felt extremely confident in receiving honest and complete information about vaccination from doctors/ pediatricians but also from the experience of other parents. The objective of this study was to investigate the influence of parental knowledge of vaccines and vaccination in Albania.
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